Women, particularly minority women, are increasingly represented in the ranks of the HIV-infected. With effective antiretroviral therapy, they are transitioning through menopause and surviving into middle and old age. The adverse musculoskeletal effects of estrogen deficiency may be potentiated in HIV infection, since T cells play a fundamental role in the mechanisms by which estrogen deficiency causes early postmenopausal bone loss. There is increasing evidence that HIV+ women may be at higher risk for clinical features of musculoskeletal senescence - frailty, falls and fracture. We hypothesize that in premenopausal women, estrogen attenuates the adverse effects of HIV infection on the skeleton and muscle, and that the combined effects of declining estrogen levels associated with menopause and persistent T cell activation associated with HIV infection may accelerate bone remodeling and loss of bone and muscle mass to a greater extent in HIV+ than HIV- women. We will address this hypothesis in a longitudinal study of 330 HIV+ and HIV- women currently participating in the Women's Interagency HIV Study (WIHS). This study will extend the WIHS Metabolic Substudy to follow HIV+ and HIV- women as they transition through menopause. We will use state- of-the art and novel imaging, cell biology, and biochemical methodologies to determine the effects of the menopausal transition on bone turnover, trabecular and cortical bone density and muscle mass, functional measures of muscle strength, balance and endurance, gonadal and calciotropic hormones, pro-resorptive cytokines and T cell activation, osteoblasts and osteoclasts, to address the following specific aims: (1) To compare HIV+ and HIV- women undergoing the menopausal transition with respect to bone turnover markers and rates of trabecular and cortical bone loss;(2) To determine the effects of estrogen deficiency on T cell activation, osteoclast and osteoblast precursors and osteoblast apoptosis in HIV+ and HIV- women;(3) To compare HIV+ and HIV- women undergoing the menopausal transition with respect to changes in muscle mass, strength, and functional measures of fall risk. This study will provide clinically relevant data on loss of bone and muscle mass and fracture risk in peri- and early postmenopausal HIV+ women. Elucidation of the dominant and modulatory pathways associated with excess bone and muscle loss in aging HIV+ women is critical for future development of mechanistic, interventional studies to prevent the deleterious effects of menopause on musculoskeletal health, and will have a major impact on their clinical management. PUBLIC HEALTH RELEVANCE: As HIV-infected women are surviving into middle and old age, there is concern that they may be at higher risk of musculoskeletal senescence- frailty, falls and fracture. Bone and muscle loss that occurs with estrogen deficiency in menopause may be worse in HIV+ women. We propose a study to compare changes in bone and muscle mass, strength and fall risk in HIV+ and HIV- women undergoing the menopausal transition.